Post-acute metabolic sequelae of SARS-CoV-2 infection in nonhuman primates

非人灵长类动物感染 SARS-CoV-2 后急性代谢后遗症

基本信息

批准号：
10554898
负责人：
Paul Kievit
金额：
$ 128.66万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-31 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10554898
关键词：
2019-nCoV Acute Address Adipocytes Adipose tissue Adult Affect Antibody Therapy Antigens Attenuated Autopsy B-Lymphocytes Biopsy Bronchoalveolar Lavage C-Peptide COVID-19 COVID-19 impact COVID-19 pandemic COVID-19 patient COVID-19 severity COVID-19 survivors Cardiovascular Diseases Cells Chronic Clinical Research Coronavirus Data Development Diabetes Mellitus Dyslipidemias Endocrine Exhibits Functional disorder Future Glucose Glucose tolerance test Glycosylated hemoglobin A HIV HIV Envelope Protein gp120 Health Heterogeneity Human Hyperinsulinism Hypertension Immune Infection Inflammation Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Intervention Intestines Islet Cell Islets of Langerhans Light Lipids Liver Lung diseases Macaca mulatta Metabolic Metabolic Diseases Metabolic dysfunction Modeling Monitor Morbidity - disease rate Non-Insulin-Dependent Diabetes Mellitus Nucleic Acids Obesity Oral Pathology Peripheral Phase Population Post-Acute Sequelae of SARS-CoV-2 Infection Pre-Clinical Model Prediabetes syndrome Process Proteins Public Health Pulmonary Pathology Reporting Risk SARS-CoV-2 B.1.617.2 SARS-CoV-2 infection SARS-CoV-2 variant Sampling Therapeutic Therapeutic Agents Thinness Time Tissue Sample Tissues Toxic effect Transcript Treatment Efficacy Vaccine Therapy Vaccines Viral Viral Load result Viral Proteins Viral reservoir Viremia Virus Latency Virus Replication Virus Shedding adipokines base cell type comorbidity diet-induced obesity fasting glucose glucose metabolism insulin secretion islet lipid metabolism lymph nodes male mortality nonhuman primate novel novel therapeutic intervention pandemic disease preclinical evaluation prevent respiratory response single cell analysis single-cell RNA sequencing transcriptome variants of concern western diet

项目摘要

The COVID-19 global pandemic caused by the novel SARS-CoV-2 coronavirus continues to result in significant morbidity and mortality worldwide. Although effective vaccines and therapeutics have been introduced, COVID-19 will likely persist as a public health issue as a result of the risk of reinfection, the emergence of variants of concern that may evade current vaccines, and the potential existence of latent viral reservoirs. The risk for and the severity of COVID-19 are increased by a number of pre-existing conditions, notably diabetes, cardiovascular disease, and hypertension. Conversely, there is increasing evidence of altered glucose metabolism and new-onset diabetes as well as dyslipidemia in COVID-19 survivors, suggesting that metabolic effects of COVID-19 may comprise an important component of post-acute sequelae of COVID-19 (PASC). Thus, there is a bidirectional relationship between COVID-19 and metabolic disease, in which concurrent metabolic disease constitutes an independent comorbid factor that increases COVID-19 severity on the one hand, while SARS-CoV-2 infection exerts deleterious effects through metabolically important tissues to initiate new metabolic disease or accelerate the progression of pre-existing subclinical metabolic disease on the other. Recent studies have shown that SARS-CoV-2 can infect pancreatic islets, including b cells and other endocrine cell types, as well as adipocytes and white adipose tissue (WAT) immune cells. Based on these data, we hypothesize that SARS-CoV-2 exerts direct and indirect effects on islet and WAT function that result in the metabolic pathology associated with PACS We propose to address this hypothesis through pursuit of the following specific aim. Specific Aim1. Determine the effect of SARS-CoV-2 infection on the initiation and progression of metabolic disease. We will employ a now well-established rhesus macaque preclinical model of SARS-CoV-2 infection in which lean, metabolically healthy and obese, insulin-resistant adult male rhesus macaques will be infected with the delta variant of SARS-CoV-2 and followed for a 6-month time course, during which comprehensive longitudinal assessments of viral load, lung pathology, immune cell profiles, and glucose and lipid metabolism will be performed. Additionally, longitudinal samples of WAT immune cells and cross-sectional samples of infected and non-infected islet cells with be analyzed by single-cell RNA-seq to characterize long-term alteration of cellular profiles. At necropsy, islet function will be assessed and multiple tissue samples collected for determination of viral distribution and persistence in potential latent reservoirs. The proposed studies represent a unique opportunity to elucidate the mechanisms underlying the metabolic aspects of PASC in an experimentally tractable preclinical model that permits assessments impossible in clinical studies.

由新型 SARS-CoV-2 冠状病毒引起的 COVID-19 全球大流行继续导致全球发病率和死亡率显着。尽管已经有了有效的疫苗和治疗方法据介绍，由于存在再次感染的风险，COVID-19 可能会持续作为一个公共卫生问题，可能逃避当前疫苗的令人担忧的变体的出现，以及潜伏病毒的潜在存在水库。许多既存疾病会增加 COVID-19 的风险和严重程度，尤其是糖尿病、心血管疾病和高血压。相反，越来越多的证据表明 COVID-19幸存者的葡萄糖代谢改变和新发糖尿病以及血脂异常，表明 COVID-19 的代谢影响可能是急性后遗症的重要组成部分 COVID-19 (PASC) 的。因此，COVID-19 与代谢疾病之间存在双向关系，并发代谢疾病构成增加 COVID-19 的独立共病因素一方面严重性，而 SARS-CoV-2 感染则通过代谢产生有害影响引发新代谢疾病或加速已有亚临床疾病进展的重要组织另一方面是代谢性疾病。最近的研究表明 SARS-CoV-2 可以感染胰岛，包括 b 细胞和其他内分泌细胞类型，以及脂肪细胞和白色脂肪组织 (WAT) 免疫细胞。根据这些数据，我们假设 SARS-CoV-2 对胰岛和胰岛产生直接和间接影响 WAT 功能导致与 PACS 相关的代谢病理学我们建议解决这个问题通过追求以下特定目标的假设。具体目标 1．确定 SARS-CoV-2 感染对代谢启动和进展的影响疾病。我们将采用现已完善的 SARS-CoV-2 感染恒河猴临床前模型，其中瘦弱、代谢健康和肥胖、胰岛素抵抗的成年雄性恒河猴将感染 SARS-CoV-2 的 delta 变体，并跟踪了 6 个月的时间过程，在此期间进行了全面的纵向研究对病毒载量、肺部病理学、免疫细胞概况以及葡萄糖和脂质代谢的评估将执行。此外，WAT 免疫细胞的纵向样本和感染病毒的横截面样本和未感染的胰岛细胞，通过单细胞 RNA-seq 进行分析，以表征胰岛细胞的长期变化蜂窝配置文件。在尸检时，将评估胰岛功能并收集多个组织样本用于确定潜在潜伏病毒库中的病毒分布和持久性。拟议的研究代表这是一个独特的机会来阐明 PASC 代谢方面的潜在机制实验上易于处理的临床前模型，允许在临床研究中进行不可能的评估。